Over the past several decades, scientists have postulated that PPARγ is the generally accepted site of action for insulin sensitizing compounds.
Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor super family that are ligand-activated transcription factors regulating gene expression. PPARs have been implicated in autoimmune diseases and other diseases, i.e. diabetes mellitus, cardiovascular and gastrointestinal disease, and Alzheimer's disease.
PPARγ is a key regulator of adipocyte differentiation and lipid metabolism. PPARγ is also found in other cell types including fibroblasts, myocytes, breast cells, human bone-marrow precursors, and macrophages/monocytes. In addition, PPARγ has been found in macrophage foam cells in atherosclerotic plaques.
Thiazolidinedione compounds, developed originally for the treatment of type-2 diabetes, generally exhibit high-affinity as PPARγ ligands. The finding that thiazolidinediones might mediate their therapeutic effects through direct interactions with PPARγ helped to establish the concept that PPARγ is a key regulator of glucose and lipid homeostasis. However, compounds that involve the activation of PPARγ also trigger sodium reabsorption and other unpleasant side effects.
Brown adipose tissue (BAT) is responsible for cold- and diet-induced thermogenesis that significantly contributes to the control of body temperature and energy expenditure. Physiol Rev. 2004; 84:277-359. Literature reports indicate that BAT thermogenesis is principally dependent on the β-adrenergically mediated activation of lipolysis and subsequent degradation of fatty acids, which generates heat dependent on uncoupling protein 1 (UCP1) that uncouples mitochondrial oxidative phosphorylation to dissipate the electrochemical gradient as heat instead of ATP synthesis. Diabetes 2009; 58:1526-1531. Traditional thiazolidinediones such as pioglitazone can increase differentiation of BAT and increase BAT stores in mammals. Biochemical Pharmacology 1996; 52:639-701. However, many thiazolidinediones evaluated for clinical development were shown to activate PPARγ, which ultimately resulted in the transcription of genes favoring sodium reabsorption, fluid retention, and weight gain in patients. Guan, Y. et al., Nat. Med. (2005) 11:861-866. It is generally believed that this PPARγ agonism is also responsible for the biological activity of these compounds including the differentiation of BAT. Petrovic et al., Am. J. Physiol. Endocrinol. Meta. (2008) 295: E287-E296. Recent studies indicate that these BAT stores are inversely proportional to body mass index, which is an index of obesity. N. Engl. J. Med., 2009; 360:1500-1508.